Project Summary Pigs are physiologically, anatomically and immunologically similar to humans. Thus, they serve as a great biomedical research model. However, the inability to generate embryonic stem cells (ESCs) and somatic cell reprogrammed induced pluripotent stem cells (iPSCs) has limited the usefulness of this model species for studying human diseases and regenerative medicine. Overcoming this limitation will enhance opportunities to generate genetically-engineered lines that can be used for studying human diseases. The long-term goal of this work is to establish innovative approaches for maintaining porcine ESCs and iPSCs without the need to constitutively express pluripotency-related transcriptional factors. The innovative strategy tested in this exploratory proposal is using interleukin-6 (IL6) to maintain pluripotency in porcine cells. Interleukin-6 has not been tested as a pluripotency factor in pigs, but all indications are that it will serve in this capacity. Previous reports and recent findings provide compelling evidence that IL6 serves as a pluripotency factor in pigs, humans and other mammals. The work in this proposal will test the hypothesis that IL6 is a driver of plasticity and pluripotency in porcine ESCs and iPSCs. Two aims are planned. Aim 1 will explore the actions of IL6 acts on porcine ICM cells. The premise is that IL6 will maintain a self-renewing population of pICM cells that resemble the authentic pluripotency features of nave ESCs. Aim 2 will examine whether transgene-free porcine iPSC can be established by IL6 supplementation. Reprogramming porcine fibroblasts in the presence of IL6 is anticipated to reduce the need for transgene expression of core pluripotency factors and microRNAs that facilitate pluripotency in pigs.